Autism Spectrum Disorder and Epilepsy: Point of Convergence or Divergence

Abstract

Autism spectrum disorder (ASD) is characterized by deficits in social communication and interaction in various contexts, along with restrictive and repetitive behaviors. Individuals with ASD often have cooccurring neurodevelopmental, neuropsychiatric, and neurological disorders. The prevalence of epilepsy in ASD ranges from 2 to 60%. The notable association between autism and epilepsy highlight the shared neurobiological features in both conditions that include synaptic dysfunction, abnormalities in cell signalling and proliferation, chromatin modification and transcription, and an imbalance between excitation and inhibition. Recent advances in next-generation sequencing techniques have revealed similar etiological and molecular mechanisms underlying autism and epilepsy through the identification of various genes linked to their pathophysiological processes. Older age, female sex, the presence of intellectual disability, developmental delay, and severe symptoms of autism are risk factors for epilepsy reported in autistic individuals. In this review, we will focus on the underlying molecular mechanisms, clinical characteristics, predictive factors for developing epilepsy in autism, and the common genetic disorders associated with the ASD-epilepsy phenotype.

Key Points

• The prevalence of epilepsy in ASD ranges from 2 to 60%.

• Shared pathobiology in ASD and epilepsy involves synaptic dysfunction, abnormalities in cell signalling and proliferation, chromatin modification and transcription, and excitation and inhibition imbalance.

• Older age, female sex, the presence of intellectual disabilities, developmental delays, and severe symptoms of autism are risk factors for epilepsy in individuals with autism.

Keywords

autism - epilepsy - autism spectrum disorder - genetic - pathophysiology - ASD-epilepsy phenotype

Introduction

Autism spectrum disorder (ASD) is characterized by deficits in social communication and interaction in various contexts, along with restrictive and repetitive behaviors.[1] Individuals with ASD may also have other cooccurring neurodevelopmental disorders (NDDs) including attention deficit hyperactivity disorder (ADHD) and intellectual disability (ID).[2] [3] They are also at an increased risk for neurological disorders, such as epilepsy and sleep disturbances, as well as neuropsychiatric conditions, including anxiety, depression, and obsessive-compulsive disorder.[4] [5] While autism itself poses significant challenges, the presence of these coexisting conditions can create additional hurdles for both patients and health care providers.

Epilepsy is marked by recurrent seizures, which can be caused by structural, infectious, immune, metabolic, or genetic factors.[5] [6] The International League Against Epilepsy defines epilepsy as “the occurrence of at least two unprovoked seizures occurring more than 24 hours apart or one unprovoked seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures occurring over the next 10 years or diagnosis of an epilepsy syndrome.”[5] In individuals having autism, the frequency of epilepsy varies from 2 to 46%.[5] [7] Similarly, those with epilepsy are also more likely than the general population to have autism.[5] Kanner reported the first patient manifesting autistic traits and abnormal electroencephalogram (EEG).[8] Since then, efforts have been made to deepen our understanding of the relationship between these two conditions and to explore their common mechanistic link.

The shared etiologies and pathophysiological processes have been attributed to the high epilepsy prevalence in individuals with autism and vice versa.[5] Impaired functioning of proteins involved in cell adhesion, scaffolding, and signalling at synapses, an imbalance between excitatory and inhibitory neurotransmitters, and dysfunction of ion channels have been attributed to the pathogenesis.[2] [9] Recent advances in next-generation sequencing techniques have improved our understanding of the relationship between autism and epilepsy, revealing numerous genetic factors involved in these functions.[10] [11]

Not all individuals with autism experience seizures. When ASD and epilepsy coexist in an individual, the condition is referred to as the ASD-epilepsy (ASD-E) phenotype. Older age, female sex, the presence of ID, developmental delay, and severe symptoms of autism have a higher risk for epilepsy in autistic individuals.[11] There is currently limited literature on the molecular mechanisms, genetic factors, and clinical manifestations associated with the combined phenotype of ASD and epilepsy. Additionally, neuroimaging and electroencephalographic data regarding ASD-E presentation are scarce. This review's focus will be on the underlying molecular mechanisms, clinical characteristics, predictive factors for the development of epilepsy in autism, and common genetic disorders associated with the ASD-E phenotype.

Epidemiology

The prevalence of ASD has been steadily increasing, rising from 4 per 10,000 in early literature to about 1 in 36 children according to recent estimates from the Centers for Disease Control.[12] [13] [14] A systematic review involving 283,549 ASD patients found an epilepsy prevalence of 12.1%, with rates ranging from as low as 1.8% to as high as 60%.[15] The recent meta-analysis also estimated prevalence rates of epilepsy ranging from 9 to 19% among individuals with ASD.[16] The variability in prevalence estimates across various studies may be due to the differences in the populations assessed and the criteria used to diagnose ASD. Higher rates are often reported in studies that include children with ASD who also have intellectual disabilities.[17] [18] [19] On the other hand, very few studies have examined the prevalence of autism in persons with epilepsy. A recent meta-analysis reported a median prevalence of autism at 9% among persons with epilepsy, with a range from 0.6 to 41.9%.[15]

Pathogenesis of ASD-E phenotype

ASD and epilepsy share a common neurobiological foundation that revolves around a molecular, or rather a genetic level, pathogenesis ([Fig. 1]).[20] [21] [22] Copy number variants (CNVs), including microduplications, microdeletions, and insertions, as well as single-gene disorders, are both responsible for ASD and epilepsy.[21] Over 1,000 genes are implicated in ASD, and many of these are also associated with epilepsy.[10] [23] [24]

Fig. 1 Pathogenesis of autism and epilepsy phenotype. ASD, autism spectrum disorder; E/I, excitation/inhibition.

Defects in four key biological pathways crucial for neuronal development and function are primarily responsible for autism and epilepsy. Disease-causing variants in genes ([Table 1]) associated with transcription regulation (such as MECP2, MEF2C, UBE3A, FOXG1, and ADNP), cellular growth (including TSC1, TSC2, PTEN, and DEPDC5), ion channels (like SCN1A, SCN2A, SCN8A, KCNQ2, KCNQ3, CACNA1A, and CACNA1C), and synaptic structure (such as CDKL5, FMR1, SHANK3, NLGN, NRXN, and SYNGAP1) can lead to the development of ASD-E phenotype.[10] [23] [24] [25] [26] [27]

Table 1 Genes implicated in autism spectrum disorder-epilepsy phenotype

Molecular mechanisms	Genes
Synaptic structure and function	CDKL5, CASK, STXBP1, SHANK3, NRXN1, NLGN, PCDH19
Transcription and gene expression	MECP2, MEF2C, FOXG1, SYNGAP1, YWHAG, PACS2, ACTL6B
Ion channels	SCN1A, SCN2A, SCN8A, KCNQ1, KCNQ2, KCNB1, CACNA1A HCN1, GRIN2D
mTOR pathways	TSC1, TSC2, PI3K-AKT, GATOR1 complex (DEPDC5, NPRL2, NPRL3)

Abbreviation: mTOR, mammalian target of rapamycin.

Note: This table does not represent an exhaustive list of all relevant genes.

Ion Channel Dysfunction

Variations in genes encoding voltage-gated and ligand-gated ion channels have been linked to ASD-E phenotype. Specifically, mutations in the SCN1A, SCN2A, and SCN8A genes, which encode voltage-gated sodium channel subunits, as well as KCNQ2/3 genes, encoding voltage-gated potassium channel subunits, can cause both ASD and epilepsy.[24] The increased excitability caused by dysfunctional ion channels that mediate depolarization, such as sodium channelopathies, or a decrease in inhibitory function due to potassium channelopathies or GABAergic alterations, leads to an excitatory-inhibitory imbalance, which contributes to the development of ASD-E phenotype.[23] [24]

Transcription and Chromatin Remodeling Alterations

Epigenetic modifications that influence deoxyribonucleic acid transcription are important factors in the development of ASD-E. Key genes involved in these mechanisms include SYNGAP1, MECP2, MEF2C, and FOXG1.[10] [23] [24] Alterations in these genes can result in altered chromatin remodeling and ribonucleic acid (RNA) splicing, which contribute to the complex pathophysiology of ASD-E.

Neuronal Cell Proliferation Dysregulation

In the early stages of brain development, the dysregulation of cellular proliferation, a critical process in brain development, leads to aberrant neuronal cytoarchitecture and, consequently, altered neural connections.[25] [26] [27] The mTOR (mammalian target of rapamycin) signaling pathway has a crucial role in cell growth, survival, and proliferation. Specifically, mTORC1 operates downstream of proteins encoded by the genes PTEN, TSC1, and TSC2, which are associated with epilepsy and ASD and are implicated in Cowden syndrome and tuberous sclerosis complex (TSC) syndrome, respectively.[26] Since mTOR controls the number and structure of synapses, white matter connectivity, the growth of GABAergic interneurons, and neuronal cell morphology, disruptions in these pathways contribute to ASD-E phenotype.

Synaptic Plasticity Dysfunction

Synaptic plasticity has a pivotal role in memory, learning, and neurodevelopment and is also essential for maintaining excitation and inhibition (E/I) balance within the brain.[28] [29] Neuronal hyperexcitability is a telltale sign of autism and epilepsy, and both these disorders have elevated glutamatergic activity.[28] Dysmorphic dendritic spines are another feature observed in ASD and epilepsy.[30] [31] Additionally, cell adhesion molecules (CAMs) are vital for developing and maintaining synaptic connections. These components include the presynaptic neurexins (NRXN1-3), postsynaptic adhesion partners neuroligins (NLGN1-4), and the SHANK family of postsynaptic proteins. Other important CAMs include contactin (CNTN) and contactin-associated proteins (CNTNAP), which are crucial to the molecular organization of axons and dendrites. Among these, NRXN1, NLGN3, SHANK3, and CNTNAP2 are strongly linked to ASD-E phenotype.[24] [31]

Excitation-Inhibition (E/I) Imbalance

Disinhibition of inhibitory signaling, combined with an increase in excitatory pathways, leads to an imbalance between excitation and inhibition in the cortex. This imbalance is a common factor in both epilepsy and autism. Increased excitation has been attributed to enhanced excitatory neurotransmission, which involves an increase in glutamate release or changes in glutamate receptor subunit.[24] GABA is an inhibitory neurotransmitter and plays a crucial role in the development of immature cortical networks in the brain. Abnormal GABAergic signaling is another mechanism linked to both autism and epilepsy, supported by animal studies showing a reduction of GABA receptors in the cortex.[26] Ultimately, these changes in E/I balance make the network more prone to dysrhythmia, seizures, and the behaviors observed in ASD.[24] [26]

Clinical Characteristics of ASD-E

The occurrence of epilepsy in ASD often peaks during early childhood and adolescence.[11] [32] [33]

A recent long-term prospective study involving 150 ASD children found that 22% developed epilepsy, with most experiencing onset after age 10.[11] Although males are diagnosed with ASD four times more often than females, this ratio decreases to 2:1 in those with ASD-E phenotype.[2] [15] [18] Notably, epilepsy is nearly twice as prevalent in girls with ASD under 12 compared to boys (34.5% vs. 18.5%, respectively).[18] This discrepancy may be due to the underlying causative genetic influences in females that predispose them to epilepsy.[6]

ID is the most common NDD that coexists with ASD and epilepsy. Various studies have demonstrated that individuals with ASD and ID had higher rates of epilepsy.[11] [18] [20] [22] [32] [33] Moreover, those individuals with ASD having higher intelligence quotient had lower odds of developing epilepsy.[11] Children with ASD-E phenotype exhibit higher levels of hyperactivity before seizure onset and have been reported to have lower adaptive functioning.[6] [22]

Developmental regression occurs in about one-third of ASD children, typically between 18 and 24 months of age.[34] Studies have indicated that children with ASD who experience regression may have higher rates of seizures. Autistic regression refers to a decline in social communication skills such as making eye contact, pointing, gesturing, and previously acquired language.[11] In the presence of regression in ASD, it is essential to differentiate autism regression from epileptic aphasia ([Table 2]), which affects school-age or older children with normal development.[35] [36] [37] [38] [39] Landau–Kleffner syndrome is an epileptic aphasia syndrome characterized by subacute onset loss of acquired language skills, often accompanied by infrequent seizures and behavioral changes.[38] Language regression typically begins with a decline in receptive skills followed by expressive skills and can often be mistaken for deafness initially. Epileptiform activity is predominantly seen over the posterior temporal and parietal lobes and often demonstrates electrical status epilepticus pattern in sleep.[38] [39]

Table 2 Distinguishing features of regression in autism and Landau–Kleffner syndrome[35] [36] [37] [38] [39]

Clinical characteristics	Autistic regression	Landau–Kleffner syndrome
Initial development	Normal or delay in language and/or social domains	Usually normal
Regression	Plateauing or decline in language and social communication skills (autistic regression)	Auditory verbal agnosia and acquired epileptic aphasia; loss of expressive language over days to weeks
Age at regression	Usually between 18 and 24 months of age	Between 3 and 8 years of age
Behavioral patterns	Loss of eye contact, name call response, gesturing and pointing, restricted repetitive behaviors, echolalia, jargon speech, and sensory sensitivities	Language regression, behavioral problems such as hyperactivity, irritability, and inattention; occasionally social withdrawal and features of autism
Seizures	Unlikely as the presenting symptom	Seizures usually precede the regression
EEG findings	Normal or focal/multifocal/generalized epileptiform discharges	Frequent activation of epileptiform discharges during sleep in temporal regions or electrical status epilepticus in sleep (ESES) pattern

Abbreviation: EEG, electroencephalography.

Neuropsychiatric symptoms can pose significant challenges for individuals with ASD or epilepsy, and these symptoms are more common when both conditions are present together.[40] [41] Studies have shown that between 70 and 96% of individuals diagnosed with ASD also have at least one cooccurring psychiatric disorder such as ADHD, anxiety, depression, mood disorders, and obsessive-compulsive disorder.[40] Similarly, it is estimated that 30 to 50% of individuals with epilepsy experience psychiatric comorbidities with depression and anxiety being the most prevalent.[41]

Epilepsy Features in ASD-E

The types of seizures in children with ASD vary widely. The most frequent are generalized tonic-clonic seizures (GTCS; 48%), followed by focal seizures (17%). Atypical absence seizures and myoclonic seizures are infrequent.[42] [43] Children with ASD may experience focal seizures that have features of self-limiting epilepsy with centrotemporal spikes.[44] There are currently no randomized control trials or cohort studies on antiseizure medications (ASMs) specifically addressing seizure management in the ASD population. However, when seizures are present, treatment is tailored to individual cases and also according to the existing guidelines for epilepsy management.[35]

EEG abnormalities are observed in 8 to 60% of individuals with ASD ([Fig. 2]). However, there are no specific patterns consistently reported in the EEG of individuals with ASD-E phenotype. These abnormalities may present as interictal epileptiform discharges (IEDs) or slowing of background activity.[6] Focal IEDs are more frequently found in the frontotemporal and centrotemporal regions. It is worth noting that epileptiform discharges can occur even in the absence of clinical seizures ([Fig. 3]).[44] [45] [46] Current guidelines do not recommend routine acquisition of EEG in ASD unless there is clinical suspicion of seizures or evidence of developmental regression and to rule out acquired epileptic aphasia.[6] [35] There is also no recommendation for treating an ASD individual with ASMs in the absence of clinical seizures. While some clinical characteristics can help predict the future occurrence of seizures in individuals with ASD, the use of EEG as a predictive tool is not well researched ([Table 3]).[47]

Fig. 2 A 9-year-old boy with Angelman syndrome presented with atonic seizures and autism. Electroencephalogram (EEG) shows low–medium amplitude spike and wave discharges predominantly in the Fp1-F3 and Fp1-F7 channels (red arrow), and polymorphic sharps are seen in the posterior head region (left > right) (black arrows).

Fig. 3 Electroencephalogram (EEG) of a 7-year-old girl with Rett syndrome without any clinical seizures showing electrical status epilepticus in sleep.

Table 3 Predictors of epilepsy in autism[33]

Behavioral/psychiatric disorders Intellectual disability Female gender Developmental regression Older age Severe language difficulties Positive family history of epilepsy Genetic causes

Genetic Syndromes Associated with ASD-E

Some genetic disorders alter the synaptic plasticity and E/I balance, which can result in both autism and epilepsy. Structural chromosomal abnormalities, including deletions and duplications, and single gene disorders such as Rett syndrome, CDKL deficiency disorders, fragile X mental retardation syndrome, TSC, etc. ([Table 4]), are the most common conditions causing ASD-E phenotype.[29] Several CNVs, both inherited and de novo, have been linked to ASD as well as epilepsy. Some of the most common CNVs associated with these conditions include deletions or duplications at the following chromosomal regions: 1q21.1, 2p16.3, 7q11.23, 15q11–q13, 16p11.2, and 22q11.21.[48] [49] Some of these disorders are described in this section.

Table 4 Clinical characteristics of common single gene disorders causing ASD-E phenotype

Gene	Clinical phenotype
SCN1A[86]	Dravet syndrome, DEE, GEFS + , MAE, ASD in 20–40%, movement disorders, ataxia, normal cognition to severe ID
SCN2A[87]	DEE, neonatal seizures, benign familial infantile seizures, mild to severe ID, ataxia, ASD
SCN8A[88]	DEE, benign familial infantile seizures, ASD, behavioral problems, movement disorders, normal cognition to severe ID
KCNB1[89]	85% with epilepsy, language difficulties, behavioral problems, movement disorders
SHANK3[90]	Phelan–McDermid syndrome characterized by global developmental delay, absent to severely delayed speech, ASD in 100%, ID, facial dysmorphism (deep set eyes, long eyelashes, bulbous nose, and pointed chin), and epilepsy in 30% (atypical absence, tonic and atonic seizures)
MECP2[66] [68]	Epilepsy in 63%, ASD in 100%, ID, microcephaly, hypotonia followed by spasticity and breathing problems
MEF2C[73] [74]	ID, ASD, facial dysmorphism and myoclonic seizures, epileptic spasms and atypical absences
TSC1, TSC2[60] [61] [62] [63] [64] [65]	ID (20–50%), epilepsy (75–80%), ASD (16–20%), ADHD (16–57%), cardiac rhabdomyomas (39–52%), renal manifestations (15–58%), dermatological manifestations (55–76%)
FMR1[58]	Fragile X syndrome characterized by facial dysmorphism (long face, large ears, and prominent jaw), moderate-to-severe ID, and macroorchidism in puberty
PTEN[91] [92]	Macrocephaly, ASD, mucocutaneous lesions, and hamartoma syndromes
CDKL5[69] [70] [71] [72]	DEE, postnatal microcephaly, stereotypic hand movements, ID, cortical visual impairment, hypotonia, autonomic disturbances, and movement disorders including chorea and dystonia
CASK[75] [76]	Microcephaly, developmental delay, growth retardation, pontine and cerebellar hypoplasia, and eye abnormalities

Abbreviations: ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; ASD-E, combined autism and epilepsy phenotype; DEE, developmental epileptic encephalopathy; GEFS + , genetic epilepsy with febrile seizure + ; ID, intellectual disability; MAE, myoclonic astatic epilepsy.

Genomic Disorders

Maternal 15q duplication syndrome is one of the most common chromosomal abnormalities associated with autism and epilepsy. This syndrome arises from the reciprocal duplications of chromosome 15q11–q13 inherited from the mother. In contrast, a deletion of this region, known as the Prader–Willi/Angelman critical region, can cause either Prader–Willi syndrome (PWS) or Angelman syndrome (AS).[50] The clinical features of maternal 15q duplication syndrome include developmental delays, hypotonia, facial dysmorphism, ID, ASD, and epilepsy.[50] [51] Typical facial dysmorphism observed are depressed nasal bridge, down-slanting palpebral fissures, low-set ears, long philtrum, micrognathia, thick vermilion of the upper and lower lips, flat occiput, and high-arched palate. Approximately half of these children may develop epilepsy, and multiple seizure types are reported, such as epileptic spasms and myoclonic, tonic-clonic, absence, and focal seizures.[51] Genes encoding GABA receptor subunits such as GABRA5, GABRB3, and GABRG3 are present within the duplicated 15q11-q13 region, and this can result in the deregulation of inhibitory synapses and contribute to the development of epilepsy and autism.[52]

AS results from a dysfunction in the UBE3A gene, often due to a maternal deletion of the 15q11-13 region. Other causes are due to point mutation in the maternal UBE3A allele (5–10%), imprinting defect (3–5%), and paternal uniparental disomy (2–3%).[53] [54] Developmental deficits, autism, hypotonia, frequent laughter episodes, ataxia, and epilepsy characterize this condition.[53] Refractory childhood-onset seizures occur in 70 to 90% of patients and are more common in those with deletions compared to those with point mutations.[54] The most frequent seizure types are myoclonic and atypical absences. Affected individuals are more susceptible to seizures triggered by fever and are also more prone to nonconvulsive status epilepticus. A severe reduction in GABA signalling, synaptic dysfunction, and neuronal morphological immaturity contribute to the ASD-E phenotype in this disorder.[53]

Individuals with Down syndrome (DS) often have comorbid ID, with approximately 16 to 18% also diagnosed with ASD.[55] In children and adolescents with DS, the prevalence of epilepsy is reported to be around 8%. The types of seizures include focal seizures, epileptic spasms, and GTCS. The risk of developing epilepsy increases after the age of 40, typically presenting as late-onset myoclonic epilepsy, which is associated with the onset of symptomatic Alzheimer's disease.[56] [57] The increased risk of seizures in DS can be attributed to several factors. These include underdevelopment of the frontal and temporal lobes, abnormal cortical neuronal lamination, reduced density of inhibitory interneurons, and dysfunction of ion channels, particularly GluR5. Additionally, metabolic comorbidities and hypoxic damage to the brain resulting from congenital heart disease can also contribute to the development of epilepsy.[57]

Single Gene Disorders

Fragile X Syndrome

Among the genetic causes of ID, Fragile X syndrome (FXS) is the most common. The estimated prevalence rate is 1 in 4,000 males. About one-third of children with FXS exhibit features of autism and delayed speech. Characteristic facial features include a long face, large ears, and a prominent jaw. Other physical features include hyperflexible fingers and enlarged testes after puberty. Approximately 10 to 20% of individuals with FXS also experience epilepsy, which typically presents as focal seizures that resemble self-limiting epilepsy of childhood. EEG, in these cases, often shows the characteristic centrotemporal spikes. However, GTCS may also occur.[58]

FXS is a CGG trinucleotide repeat disorder, causing inactivation of the FMR1 gene. This leads to the loss of expression of fragile X mental retardation protein (FMRP), an RNA-binding protein that localizes to dendritic ribosomes. This protein plays a crucial role in synaptic remodeling, which is necessary for learning and memory.[58] The excessive activation of mGluR5 due to poor FMRP translational control has been proposed as a possible underlying mechanism for epilepsy.[59]

Tuberous Sclerosis Complex

TSC is an autosomal dominant disorder characterized by various neurological manifestations, behavioral issues, multisystem involvement, and tumor formation. This condition results from hyperactivation of the mTORC1 pathway, caused by either de novo or inherited inactivating mutations in the TSC1 or TSC2 genes.[60] In the developing brain, the mTORC1 signalling pathway is essential for controlling cellular processes such as cell migration, growth, and proliferation. When this pathway is dysregulated, it can disrupt the balance between excitation and inhibition, leading to epilepsy and developmental impairments.[61]

Tuberous sclerosis-associated neuropsychiatric disorders encompass a broad range of cognitive and psychological features seen in individuals with TSC.[62] ASD affects approximately 26 to 50% of patients with TSC.[63] The prevalence of epilepsy in TSC patients ranges from 62 to 93%.[64] Although various types of seizures can occur in TSC, the most common are epileptic spasms and focal seizures.[62] Other seizures, such as atonic, tonic, and tonic-clonic seizures, may also be present.[64] Most patients experience seizure onset in the first few months of life, typically before reaching 1 year of age, and 38 to 50% of them have refractory epilepsy.[65] Additionally, TSC patients with ASD tend to experience a more severe epilepsy phenotype.[62]

Rett Syndrome

Loss of function in the methyl-CpG-binding protein 2 (MECP2) gene, which codes for the MeCP2 protein, results in Rett syndrome. During brain development, MeCP2 mainly acts as a transcriptional activator. The loss of MECP2 function affects glutamatergic signaling while decreasing GABAergic transmission and can lead to the clinical phenotype of Rett syndrome.[24]

Rett syndrome is an X-linked dominant disorder and females are predominantly affected.[66] [67] [68] The clinical features include ID, postnatal microcephaly, loss of spoken language, stereotypic hand movements, autism, and loss of acquired purposeful hand use. Initially, development appears normal, but regression occurs between 6 and 18 months of age. Other manifestations include gait impairment, breathing disturbances, peripheral vasomotor disturbances, eye-pointing, and cardiac complications. Seizures are reported in 50 to 90% of individuals with Rett syndrome, which typically occurs after the age of 2.[66] [67] The severity and type of seizures vary in individual patients and may improve after adolescence. Those with T158M and R106W variants have been shown to have a higher predisposition to epilepsy.[67]

CDKL5 Deficiency Disorder

CDKL5 deficiency disorder (CDD) is caused by harmful variations in the CDKL5 gene and has an X-linked dominant inheritance pattern. This condition belongs to the broader category of developmental and epileptic encephalopathy and is distinguished by early-onset, refractory seizures and severe developmental deficits. In addition, they also have features of autism, stereotypical movements of hands, marked hypotonia, cortical visual impairment, movement disorders (chorea and dystonia), and autonomic disturbances.[69] [70] CDKL5 interacts with MeCP2, which explains the shared clinical manifestations between CDD and Rett syndrome. Females are more frequently affected than males, but the severity of the disorder is similar across both sexes.[69]

The most frequent initial seizure type is epileptic spasms, which occur in nearly 25% of children with CDD; however, the types of seizures can vary with age. Focal, myoclonic, tonic, and GTCS are also reported in this condition. Hypermotor-tonic spasms are a distinct seizure observed in CDD and is characterized by phases of spasms, tonic seizures, and hypermotor activity. Generally, epilepsy associated with CDD is medically refractory throughout life, but some children may experience temporary improvements, often referred to as a “honeymoon period,” typically occurring between 1 and 2 years of age.[71] [72]

MEF2C-Related Disorder

The clinical features of MEF2C-related disorders include developmental delay, ID, limited language ability, hypotonia, and seizures. Loss-of-function of MEF2C due to microdeletions of chromosome 5q14.3 or point mutations can cause this condition. MEF2C has diverse functions in brain development, particularly in cortical lamination. It also regulates the expression of several genes that are crucial for synaptic development and function via synaptic activity-response element.[73]

More than 80% of children were reported to have seizures, limited speech, bruxism, repetitive movements, and high pain tolerance. Only one-fourth of children were diagnosed with ASD in this condition.[73] The types of epilepsy reported in MEF2C-related disorders were epileptic spasms (20%), infantile-onset myoclonic epilepsy (33%), and childhood-onset generalized epilepsy (24%).[74] The other seizure types reported were absence, atonic, and atypical complex febrile seizures. Seizures were refractory only in around 16%.[73]

CASK-Related Disorders

In the brain, the expression of a calcium/calmodulin-dependent serine protein kinase (CASK) is another essential protein needed for synapse development and cortical growth. Females with mutations in the CASK gene display specific features such as growth retardation, developmental delay, ID, ASD, postnatal microcephaly, pontine and cerebellar hypoplasia, as well as eye abnormalities and facial dysmorphisms. About half of them experience seizures, which include epileptic spasms, generalized or focal seizures, typically beginning at or after the age of 2. These seizures are often resistant to treatment in at least half of those with epilepsy.[75] In contrast, male patients with hypomorphic CASK genes tend to exhibit a milder phenotype.[76]

FOXG1-Related Disorder

Pathogenic single-allele variants in the FOXG1 (Forkhead box G1) gene can cause a clinical syndrome of severe developmental delay, ID, ASD, absent speech, postnatal microcephaly, hypotonia, sleep disorders, and hyperkinetic movement disorders.[77] [78] This condition was initially termed as “congenital variant of Rett syndrome.”[78] Corpus callosum anomalies, simplified gyral pattern, thickening of the fornices, and hypoplasia of the basal ganglia and frontal lobes are the neuroimaging features described in this disorder.[77] Seizures were documented in approximately three-quarters of patients, and GTCS were more frequent. Half of them had refractory epilepsy and had multiple seizure types.[78]

Children with FOXG1 duplications on chromosome 14q12 also exhibit severe epilepsy syndrome characterized by epileptic spasms, which respond to adrenocorticotropin administration.[79] [80] However, they often experience long-term developmental impairments, including autism.[77]

Genetic Diagnosis in ASD-E

Current guidelines recommend that all patients with ASD undergo genetic evaluation. The first-tier investigation recommended for ASD and other NDDs is chromosomal microarray analysis (CMA).[81] The American College of Medical Genetics also suggests FMR1 testing in males, PTEN testing in children with macrocephaly, and MECP2 testing in those with regression, as other first-tier investigations.[82] CMA is less favored as the primary genetic test for childhood-onset epilepsy of presumed genetic basis due to a low diagnostic yield of 5 to 18%. Exome sequencing is recommended instead, which has a higher yield of 24 to 45%.[83] A similar shift has been observed in the genetic testing for ASD, with several large-scale studies reporting a diagnostic yield of 39 to 75%.[82] [84] There are no studies that have explored the diagnostic yield of the combined phenotype of ASD-E. Nonetheless, the choice of genetic testing for a child with ASD and epilepsy should be based on the clinical profile along with family history and results from radiological, electrophysiological, and metabolic evaluations.

In one study, the diagnostic yield of exome sequencing in NDDs was reported to be 41%.[85] Genetic evaluation is commonly pursued in children with ASD-E phenotype, as well as for ASD children who have global developmental delay, regression, macrocephaly or microcephaly, facial dysmorphism, a strong family history of genetic disorders, or when supportive investigations indicate a potential genetic cause. Exome sequencing is often the preferred first-line genetic investigation. CMA is considered when a patient displays facial dysmorphism, skeletal abnormalities, or involvement of other organs, or when chromosomal structural alterations are suspected. Polymerase chain reaction testing for FMR1 and multiplex ligation-dependent probe amplification-methylation analysis for AS/PWS are sent when the clinical phenotype indicates these conditions. If exome sequencing yields negative results, CMA is then performed as a second-line investigation, and vice versa.

Conclusion

Autism and epilepsy indeed seem to be closely related, sharing a common pathophysiological background. Certain genetic conditions can predispose individuals to both autism and epilepsy. Well-established risk factors for epilepsy in individuals with ASD include older age, lower intellectual functioning, and female sex. However, the literature is limited on the clinical, radiological, and EEG parameters that predispose ASD individuals to developing epilepsy. More research is needed in this specific subtype of autism to enhance our understanding of the molecular mechanisms, genetic factors, and clinical indicators, as well as neuroimaging and EEG features that could predict the risk of epilepsy.

Conflict of Interest

None declared

Authors' Contributions

K.A.V.: Drafting of manuscript.

S.S.: Concept, drafting, and critical revision of manuscript.

• References

• 1 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed.. Washington, DC: American Psychiatric Association; 2013
• 2 Lord C, Brugha TS, Charman T. et al. Autism spectrum disorder. Nat Rev Dis Primers 2020; 6 (01) 5
• 3 Thapar A, Cooper M, Rutter M. Neurodevelopmental disorders. Lancet Psychiatry 2017; 4 (04) 339-346
• 4 Al-Beltagi M. Autism medical comorbidities. World J Clin Pediatr 2021; 10 (03) 15-28
• 5 Fisher RS, Cross JH, French JA. et al. Operational classification of seizure types by the International League Against Epilepsy: position paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017; 58 (04) 522-530
• 6 Capal JK, Jeste SS. Autism and epilepsy. Pediatr Clin North Am 2024; 71 (02) 241-252
• 7 Jokiranta E, Sourander A, Suominen A, Timonen-Soivio L, Brown AS, Sillanpää M. Epilepsy among children and adolescents with autism spectrum disorders: a population-based study. J Autism Dev Disord 2014; 44 (10) 2547-2557
• 8 Kanner L. The specificity of early infantile autism. Z Kinderpsychiatr 1958; 25 (1-2): 108-113
• 9 Zahra A, Wang Y, Wang Q, Wu J. Shared etiology in autism spectrum disorder and epilepsy with functional disability. Behav Neurol 2022; 2022: 5893519
• 10 Peng J, Zhou Y, Wang K. Multiplex gene and phenotype network to characterize shared genetic pathways of epilepsy and autism. Sci Rep 2021; 11 (01) 952
• 11 Viscidi EW, Johnson AL, Spence SJ, Buka SL, Morrow EM, Triche EW. The association between epilepsy and autism symptoms and maladaptive behaviors in children with autism spectrum disorder. Autism 2014; 18 (08) 996-1006
• 12 Baxter AJ, Brugha TS, Erskine HE, Scheurer RW, Vos T, Scott JG. The epidemiology and global burden of autism spectrum disorders. Psychol Med 2015; 45 (03) 601-613
• 13 Baird G, Simonoff E, Pickles A. et al. Prevalence of disorders of the autism spectrum in a population cohort of children in South Thames: the Special Needs and Autism Project (SNAP). Lancet 2006; 368 (9531): 210-215
• 14 Maenner MJ, Warren Z, Williams AR. et al. Prevalence and characteristics of autism spectrum disorder among children aged 8 years - Autism and Developmental Disabilities Monitoring Network, 11 sites, United States, 2020. MMWR Surveill Summ 2023; 72 (02) 1-14
• 15 Lukmanji S, Manji SA, Kadhim S. et al. The co-occurrence of epilepsy and autism: a systematic review. Epilepsy Behav 2019; 98 (Pt A): 238-248
• 16 Liu X, Sun X, Sun C. et al. Prevalence of epilepsy in autism spectrum disorders: a systematic review and meta-analysis. Autism 2022; 26 (01) 33-50
• 17 Matsuo M, Maeda T, Sasaki K, Ishii K, Hamasaki Y. Frequent association of autism spectrum disorder in patients with childhood onset epilepsy. Brain Dev 2010; 32 (09) 759-763
• 18 Amiet C, Gourfinkel-An I, Bouzamondo A. et al. Epilepsy in autism is associated with intellectual disability and gender: evidence from a meta-analysis. Biol Psychiatry 2008; 64 (07) 577-582
• 19 Arora NK, Nair MKC, Gulati S. et al. Neurodevelopmental disorders in children aged 2-9 years: population-based burden estimates across five regions in India. PLoS Med 2018; 15 (07) e1002615
• 20 Volkmar FR, Nelson DS. Seizure disorders in autism. J Am Acad Child Adolesc Psychiatry 1990; 29 (01) 127-129
• 21 Besag FMC, Vasey MJ. Seizures and epilepsy in autism spectrum disorder. Psychiatr Clin North Am 2021; 44 (01) 51-68
• 22 Tuchman R. What is the relationship between autism spectrum disorders and epilepsy?. Semin Pediatr Neurol 2017; 24 (04) 292-300
• 23 Schaaf CP, Betancur C, Yuen RKC. et al. A framework for an evidence-based gene list relevant to autism spectrum disorder. Nat Rev Genet 2020; 21 (06) 367-376
• 24 Specchio N, Di Micco V, Trivisano M, Ferretti A, Curatolo P. The epilepsy-autism spectrum disorder phenotype in the era of molecular genetics and precision therapy. Epilepsia 2022; 63 (01) 6-21
• 25 Keller R, Basta R, Salerno L, Elia M. Autism, epilepsy, and synaptopathies: a not rare association. Neurol Sci 2017; 38 (08) 1353-1361
• 26 Sierra-Arregui T, Llorente J, Giménez Minguez P, Tønnesen J, Peñagarikano O. Neurobiological mechanisms of autism spectrum disorder and epilepsy, insights from animal models. Neuroscience 2020; 445: 69-82
• 27 Karunakaran S, Menon RN, Nair SS, Santhakumar S, Nair M, Sundaram S. Clinical and genetic profile of autism spectrum disorder-epilepsy (ASD-E) phenotype: two sides of the same coin!. Clin EEG Neurosci 2020; 51 (06) 390-398
• 28 Bozzi Y, Provenzano G, Casarosa S. Neurobiological bases of autism-epilepsy comorbidity: a focus on excitation/inhibition imbalance. Eur J Neurosci 2018; 47 (06) 534-548
• 29 Brooks-Kayal A. Epilepsy and autism spectrum disorders: are there common developmental mechanisms?. Brain Dev 2010; 32 (09) 731-738
• 30 Lima Caldeira G, Peça J, Carvalho AL. New insights on synaptic dysfunction in neuropsychiatric disorders. Curr Opin Neurobiol 2019; 57: 62-70
• 31 Rylaarsdam L, Guemez-Gamboa A. Genetic causes and modifiers of autism spectrum disorder. Front Cell Neurosci 2019; 13: 385
• 32 Bolton PF, Carcani-Rathwell I, Hutton J, Goode S, Howlin P, Rutter M. Epilepsy in autism: features and correlates. Br J Psychiatry 2011; 198 (04) 289-294
• 33 Deykin EY, MacMahon B. The incidence of seizures among children with autistic symptoms. Am J Psychiatry 1979; 136 (10) 1310-1312
• 34 Barger BD, Campbell JM, McDonough JD. Prevalence and onset of regression within autism spectrum disorders: a meta-analytic review. J Autism Dev Disord 2013; 43 (04) 817-828
• 35 Frye RE, Rossignol D, Casanova MF. et al. A review of traditional and novel treatments for seizures in autism spectrum disorder: findings from a systematic review and expert panel. Front Public Health 2013; 1: 31
• 36 Mantovani JF. Autistic regression and Landau-Kleffner syndrome: progress or confusion?. Dev Med Child Neurol 2000; 42 (05) 349-353
• 37 Muzio MR, Cascella M, Al Khalili Y. Landau-Kleffner syndrome. In: StatPearls. Treasure Island, FL: StatPearls Publishing; July 3, 2023
• 38 Zafari A, Karimi N, Taherian M, Taherian R. Landau Kleffner syndrome and misdiagnosis of autism spectrum disorder: a mini-review. Int Clin Neurosci J [Internet] 2018; 5 (01) 3-6
• 39 Kleffner FR, Landau WM. The Landau-Kleffner syndrome. Epilepsia 2009; 50 (Suppl. 07) 3
• 40 Simonoff E, Pickles A, Charman T, Chandler S, Loucas T, Baird G. Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a population-derived sample. J Am Acad Child Adolesc Psychiatry 2008; 47 (08) 921-929
• 41 Lin JJ, Mula M, Hermann BP. Uncovering the neurobehavioural comorbidities of epilepsy over the lifespan. Lancet 2012; 380 (9848): 1180-1192
• 42 Sharma V, Saini AG, Malhi P, Singhi P. Epilepsy and EEG abnormalities in children with autism spectrum disorders. Indian J Pediatr 2022; 89 (10) 975-982
• 43 Tuchman RF, Rapin I, Shinnar S. Autistic and dysphasic children. II: epilepsy. Pediatrics 1991; 88 (06) 1219-1225
• 44 Rossi PG, Parmeggiani A, Bach V, Santucci M, Visconti P. EEG features and epilepsy in patients with autism. Brain Dev 1995; 17 (03) 169-174
• 45 Chez MG, Chang M, Krasne V, Coughlan C, Kominsky M, Schwartz A. Frequency of epileptiform EEG abnormalities in a sequential screening of autistic patients with no known clinical epilepsy from 1996 to 2005. Epilepsy Behav 2006; 8 (01) 267-271
• 46 Parmeggiani A, Barcia G, Posar A, Raimondi E, Santucci M, Scaduto MC. Epilepsy and EEG paroxysmal abnormalities in autism spectrum disorders. Brain Dev 2010; 32 (09) 783-789
• 47 Zarakoviti E, Shafran R, Skuse D. et al. Factor associated with the occurrence of epilepsy in autism: a systematic review. J Autism Dev Disord 2023; 53 (10) 3873-3890
• 48 Vicari S, Napoli E, Cordeddu V. et al. Copy number variants in autism spectrum disorders. Prog Neuropsychopharmacol Biol Psychiatry 2019; 92: 421-427
• 49 Ivanisevic J. A guide to genetic testing in pediatric epilepsy: a review of the latest genetic testing methods utilized for the diagnosis of pediatric epilepsy, with a special emphasis on the timing, value, utility, and accessibility of pediatric genetic testing. Pract Neurol 2023. Available at: https://practicalneurology.com/diseases-diagnoses/epilepsy-seizures/a-guide-to-genetic-testing-in-pediatric-epilepsy/32051/
• 50 Lusk L, Vogel-Farley V, DiStefano C. et al. Maternal 15q Duplication Syndrome. June 16, 2016 [Updated 2021 Jul 15]. In: Adam MP, Feldman J, Mirzaa GM. et al., eds. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 1993–2024
• 51 Conant KD, Finucane B, Cleary N. et al. A survey of seizures and current treatments in 15q duplication syndrome. Epilepsia 2014; 55 (03) 396-402
• 52 Paciorkowski AR, Thio LL, Rosenfeld JA. et al. Copy number variants and infantile spasms: evidence for abnormalities in ventral forebrain development and pathways of synaptic function. Eur J Hum Genet 2011; 19 (12) 1238-1245
• 53 Samanta D. Epilepsy in Angelman syndrome: a scoping review. Brain Dev 2021; 43 (01) 32-44
• 54 Cassater D, Bustamante M, Sach-Peltason L. et al. Clinical characterization of epilepsy in children with Angelman syndrome. Pediatr Neurol 2021; 124: 42-50
• 55 Richards C, Jones C, Groves L, Moss J, Oliver C. Prevalence of autism spectrum disorder phenomenology in genetic disorders: a systematic review and meta-analysis. Lancet Psychiatry 2015; 2 (10) 909-916
• 56 d'Orsi G, Specchio LM. Apulian Study Group on Senile Myoclonic Epilepsy. Progressive myoclonus epilepsy in Down syndrome patients with dementia. J Neurol 2014; 261 (08) 1584-1597
• 57 Altuna M, Giménez S, Fortea J. Epilepsy in Down syndrome: a highly prevalent comorbidity. J Clin Med 2021; 10 (13) 2776
• 58 Berry-Kravis E, Filipink RA, Frye RE. et al; FORWARD Consortium. Seizures in Fragile X syndrome: associations and longitudinal analysis of a large clinic-based cohort. Front Pediatr 2021; 9: 736255
• 59 Bianchi R, Chuang SC, Zhao W, Young SR, Wong RK. Cellular plasticity for group I mGluR-mediated epileptogenesis. J Neurosci 2009; 29 (11) 3497-3507
• 60 Uysal SP, Şahin M. Tuberous sclerosis: a review of the past, present, and future. Turk J Med Sci 2020; 50 (SI-2): 1665-1676
• 61 Aronica E, Specchio N, Luinenburg MJ, Curatolo P. Epileptogenesis in tuberous sclerosis complex-related developmental and epileptic encephalopathy. Brain 2023; 146 (07) 2694-2710
• 62 Henske EP, Jóźwiak S, Kingswood JC, Sampson JR, Thiele EA. Tuberous sclerosis complex. Nat Rev Dis Primers 2016; 2: 16035
• 63 Conte E, Boccanegra B, Dinoi G. et al. Therapeutic approaches to tuberous sclerosis complex: from available therapies to promising drug targets. Biomolecules 2024; 14 (09) 1190
• 64 Nabbout R, Belousova E, Benedik MP. et al; TOSCA Consortium and TOSCA Investigators. Epilepsy in tuberous sclerosis complex: findings from the TOSCA Study. Epilepsia Open 2018; 4 (01) 73-84
• 65 Zhang K, Hu WH, Zhang C, Meng FG, Chen N, Zhang JG. Predictors of seizure freedom after surgical management of tuberous sclerosis complex: a systematic review and meta-analysis. Epilepsy Res 2013; 105 (03) 377-383
• 66 Collins BE, Neul JL. Rett syndrome and MECP2 duplication syndrome: disorders of MeCP2 dosage. Neuropsychiatr Dis Treat 2022; 18: 2813-2835
• 67 Glaze DG, Percy AK, Skinner S. et al. Epilepsy and the natural history of Rett syndrome. Neurology 2010; 74 (11) 909-912
• 68 Peters SU, Fu C, Marsh ED. et al. Phenotypic features in MECP2 duplication syndrome: effects of age. Am J Med Genet A 2021; 185 (02) 362-369
• 69 Olson HE, Demarest ST, Pestana-Knight EM. et al. Cyclin-dependent kinase-like 5 deficiency disorder: clinical review. Pediatr Neurol 2019; 97: 18-25
• 70 Leonard H, Downs J, Benke TA, Swanson L, Olson H, Demarest S. CDKL5 deficiency disorder: clinical features, diagnosis, and management. Lancet Neurol 2022; 21 (06) 563-576
• 71 Fehr S, Wong K, Chin R. et al. Seizure variables and their relationship to genotype and functional abilities in the CDKL5 disorder. Neurology 2016; 87 (21) 2206-2213
• 72 Amato A, Bonomo G, Bonomo R, Proietti J, Darra F. Longitudinal, multidimensional, observational study of 15 patients with CDKL5 deficiency disorder. Clin Neurol Neurosurg 2024; 246: 108603
• 73 Cooley Coleman JA, Sarasua SM, Moore HW. et al. Clinical findings from the landmark MEF2C-related disorders natural history study. Mol Genet Genomic Med 2022; 10 (06) e1919
• 74 Raviglione F, Douzgou S, Scala M. et al. Electroclinical features of MEF2C haploinsufficiency-related epilepsy: a multicenter European study. Seizure 2021; 88: 60-72
• 75 Giacomini T, Nuovo S, Zanni G. et al. CASK related disorder: epilepsy and developmental outcome. Eur J Paediatr Neurol 2021; 31: 61-69
• 76 Takanashi J, Okamoto N, Yamamoto Y. et al. Clinical and radiological features of Japanese patients with a severe phenotype due to CASK mutations. Am J Med Genet A 2012; 158A (12) 3112-3118
• 77 Brockmann K, Staudt M. FOXG1 Syndrome. Jun 6, 2024. In: Adam MP, Feldman J, Mirzaa GM. et al., eds. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 1993–2024
• 78 Vegas N, Cavallin M, Maillard C. et al. Delineating FOXG1 syndrome: from congenital microcephaly to hyperkinetic encephalopathy. Neurol Genet 2018; 4 (06) e281
• 79 Striano P, Paravidino R, Sicca F. et al. West syndrome associated with 14q12 duplications harboring FOXG1. Neurology 2011; 76 (18) 1600-1602
• 80 Pontrelli G, Cappelletti S, Claps D. et al. Epilepsy in patients with duplications of chromosome 14 harboring FOXG1. Pediatr Neurol 2014; 50 (05) 530-535
• 81 Waggoner D, Wain KE, Dubuc AM. et al; ACMG Professional Practice and Guidelines Committee. Yield of additional genetic testing after chromosomal microarray for diagnosis of neurodevelopmental disability and congenital anomalies: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med 2018; 20 (10) 1105-1113
• 82 Garrido-Torres N, Marqués Rodríguez R, Alemany-Navarro M. et al. Exploring genetic testing requests, genetic alterations and clinical associations in a cohort of children with autism spectrum disorder. Eur Child Adolesc Psychiatry 2024; 33 (11) 3829-3840
• 83 Chowdhury SR, Whitney R, RamachandranNair R, Bijarnia Mahay S, Sharma S. Genetic testing in pediatric epilepsy: tools, tips, and navigating the traps. Pediatr Neurol 2024; 157: 42-49
• 84 Srivastava S, Love-Nichols JA, Dies KA. et al; NDD Exome Scoping Review Work Group. Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders. Genet Med 2019; 21 (11) 2413-2421
• 85 Valaparambil KA, Fasaludeen A, Priya L, Menon RN, Menon R, Sundaram S. Clinical utility of proband only clinical exome sequencing in neurodevelopmental disorders. Indian J Pediatr 2025; 92 (02) 185-190
• 86 Scheffer IE, Nabbout R. SCN1A-related phenotypes: epilepsy and beyond. Epilepsia 2019; 60 (Suppl. 03) S17-S24
• 87 Reynolds C, King MD, Gorman KM. The phenotypic spectrum of SCN2A-related epilepsy. Eur J Paediatr Neurol 2020; 24: 117-122
• 88 Gardella E, Møller RS. Phenotypic and genetic spectrum of SCN8A-related disorders, treatment options, and outcomes. Epilepsia 2019; 60 (Suppl. 03) S77-S85
• 89 Bar C, Barcia G, Jennesson M. et al. Expanding the genetic and phenotypic relevance of KCNB1 variants in developmental and epileptic encephalopathies: 27 new patients and overview of the literature. Hum Mutat 2020; 41 (01) 69-80
• 90 Holder Jr JL, Quach MM. The spectrum of epilepsy and electroencephalographic abnormalities due to SHANK3 loss-of-function mutations. Epilepsia 2016; 57 (10) 1651-1659
• 91 Rademacher S, Eickholt BJ. PTEN in autism and neurodevelopmental disorders. Cold Spring Harb Perspect Med 2019; 9 (11) a036780
• 92 Yehia L, Ngeow J, Eng C. PTEN-opathies: from biological insights to evidence-based precision medicine. J Clin Invest 2019; 129 (02) 452-464

Publication History

Article published online:
13 May 2025